1. Field of Invention
The invention relates to the use of human growth hormone for the manufacture of a medicament for stimulating hematopoiesis and immune reconstitution in human patients following hematopoietic stem cell transplantation.
2. Description of the Related Art
Human growth hormone (hGH), also known as somatotropin, is a protein hormone produced and secreted by the somatotropic cells of the anterior pituitary. Human growth hormone plays a key role in somatic growth through its effects on the metabolism of proteins, carbohydrates and lipids. In addition to its effects on somatic growth, hGH has been shown to stimulate hematopoiesis (proliferation, maturation and function of erythroid, mycloid and lymphoid lineages).
The erythropoietic stimulatory effect of hGH treatment, both in healthy and in growth hormone deficient (GHD) patients has been reported in scientific publications. For instance, Valerio et al (1997) reported that, in vivo, erythropoiesis markers, such as hemoglobin (Hb), hematocrit (Ht) and red blood cell (RBC) counts, increased in GHD children following hGH therapy. Furthermore, it has been reported that increases in Hb in response to hGH treatment were similar in patients with hGH deficiency and those with normal hGH secretion (Vihervuori et al, 1996).
Moreover, recent publications show that hGH increases the proliferation and the maturation/function of the myeloid cell series. Human growth hormone enhances myeloid colony formation (Merchav et al, 1988), primes granulocyte oxidative metabolic burst in healthy and uremic children (Derfalvi et al, 1998) and enhances monocyte chemotaxis (Wiedermann et al, 1992).
Finally, several reports demonstrate that hGH exerts stimulatory effects on proliferation and maturation of the lymphoid cell series. Derfalvi et al (1998) describes that hGH administration stimulates the lymphoproliferation in healthy and uremic children, and Kimata et al (1994) determined that hGH enhances both proliferation and Ig production in plasma cell lines. Geffner (1997) mentioned that hGH has been shown to stimulate CD8+ cell counts and, to a lesser extent, CD4+ cell counts.
Bone marrow transplantation and circulating blood stem cell transplantation (hereafter both referred as hematopoietic stem cell transplantation (HSCT)) are the treatment of choice in several disorders, including malignancies, Severe Combined Immune Deficiencies (SCID), congenitally or genetically determined hematopoietic abnormalities, anemia, aplastic anemia, leukemia and osteoporosis (Fischer et al, 1998). During the past ten years, the use of HSCT grew from less than 5,000 to more than 40,000 annually (Waters et al, 1998).
Autologous HSCT defines a stem cell transplantation in which donor and recipient are the same individual. Non-autologous HSCT comprises HSCT in which donor and recipient are different individuals, either genetically identical (syngenic) or genetically different (allogenic).
Non-autologous HSCT is subject to immunological reactions, i.e., graft-versus-host disease and host-versus-graft reaction (graft rejection). The mechanisms of graft rejections are not completely known, but in addition to immune mechanisms, hematopoietic stem cells may also be rejected by natural killer (NK) cells. The recipient""s immune system must be ablated to permit successful non-autologous HSCT.
To prepare for HSCT, the recipient""s immune system is destroyed with radiation and/or chemotherapy. This procedure not only prevents non-autologous graft rejection but also serves to kill leukemic cells if that is the patient""s disease. Following HSCT, hematopoietic and immune cells of the recipients are replaced with those from the donor.
Effective treatments aimed at accelerating hematopoiesis and immune reconstitution are of great interest not only to promote engraftment but also to reduce the risk of infections and to shorten the time of hospitalization. Granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) have been shown to accelerate marrow recovery and to increase engraftment through stimulation of stem cell proliferation (Appelbaum, 1993). Similarly, recombinant human erythropoietin (rhEPO) has been shown to enhance erythroid engraftment after allogenic bone marrow transplantation and to decrease transfusion requirements (Miller et al, 1994). These growth factor treatments have demonstrated promising results in clinical trials and are currently used to improve the outcome of HSCT.
In that respect, human growth hormone represents an attractive alternative therapy since it exerts a stimulatory effect on the three hematopoietic progenitor cell series.
In rodents, it was reported that, after syngenic bone marrow transplantation in mice, hGH-treated animals exhibit significant increases in total hematopoietic progenitor cell content in both bone marrow and spleen (Tian et al, 1998). Tian et al further specified an increase in erythropoietic marker (Hb, Ht, RBC), in erythroid cell progenitor content, in granulocyte marker 8C5+ and, finally, in RBC and platelet recovery after bone marrow transplantation (BMT); and demonstrated the benefit of hGH therapy to stimulate immune reconstitution after BMT in mice. Furthermore, Tian et al suggested that hGH may be of clinical use for accelerating hematopoiesis after autologous bone marrow transplantation. The sudies leading to these results were carried out in mice. Doses of rhGH were administered to irradiated and transplanted mice after syngeneic bone marrow transplantation. The mice received the same dose of rhGH from day one every second day to a maximum of 20 days. Tian et al reported, that the hematopoietic growth-promoting effects of rhGH after SBMT did not result in toxicity or weight gain.
However, when administered to humans, human growth homone was also shown to have some drawbacks.
Human growth hormone was shown to increase the incidence of graft rejection, for instance. In growth-retarded, kidney-transplanted children, rejection episodes are more frequent in hGH treated patients than in the placebo group (Fine et al, 1991). Friedman (1997) reported that recombinant hGH treatment is not safe for children with renal transplants. Friedman argued that the hGH-mediated up-regulation of immune function could be a reason for the increased loss of renal function caused by rejection and pointed out that hGH should not be administered to children after renal allograft. In a large clinical trial assessing the results and side effects of treating children with hGH after kidney transplantation, hGH treatment was been correlated with an increased frequency of acute graft rejection, particularly in those patients who had a history of more than one episode (Johansson et al, 1990; Broyer, 1996). Finally, in liver transplantation, hGH improves growth in children receiving glucocorticoid treatment but also increases the risk of allogenic graft rejection (Sarna et al, 1996).
In the light of the data presented above, hGH therapy following HSCT carries both profitable and deleterious effects. Human growth hormone would be beneficial through its positive effect on immune reconstitution; hGH promotes proliferation of hematopoietic progenitor cells, i.e., donor stem cells, and, thus, should facilitate engraftment. Human growth hormone treatment would also provide better protection against pathogens through overall stimulation of the immune functions. However, hGH was also shown to increase the incidence of graft rejection, which is a serious drawback of its use in treating patients.
It is therefore the object of the present invention to provide a treatment for hematopoietic stem cell transplanted patients using recombinant human growth hormone to stimulate hematopoiesis and immune reconstitution, while avoiding the deleterious side effects of hGH administration, as, for example, those outlined above.
According to the present invention, human growth hormone is used for the manufacture of a medicament for stimulating hematopoiesis and immune reconstitution in human patients to be administered to humans at about 30 days post-transplantation procedure. This innovative regimen of hGH administration is intended to circumvent the graft rejection induced by hGH.
In order to provide a clearer and more consistent understanding of the specification and claims, including the scope to be given to such terms, the following definitions are provided.
Hematopoietic stem cell transplantation (HSCT): A clinical procedure in which pluripotent hematopoietic stem cells obtained from bone marrow or circulating blood are transplanted to a patient.
Bone marrow transplantation (BMT): A clinical procedure in which pluripotent hematopoietic stem cells obtained from bone marrow are transplanted to a patient.
Autologous transplantation: Transplantation in which the donor and the recipient are the same individual.
Non-autologous transplantation: Transplantation in which the donor and the recipient are different individuals from the same species, either genetically identical (syngenic transplantation) or genetically different (allogenic transplantation).